Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit. Issue 17 (15th September 2018)

• Record Type: Journal Article
• Authors: Qiu, Hui; Liu-Bujalski, Lesley; Caldwell, Richard D; Follis, Ariele Viacava; Gardberg, Anna; Goutopoulos, Andreas; Grenningloh, Roland; Head, Jared; Johnson, Theresa; Jones, Reinaldo; Mochalkin, Igor; Morandi, Federica; Neagu, Constantin; Sherer, Brian
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 17(2018)
• Page Start: 2939
• Page End: 2944
• Publication Date: 2018-09-15
• Subjects: Covalent -- Irreversible -- BTK inhibitor -- Fragment; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.07.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A novel series of potent covalent irreversible BTK inhibitors was discovered from a fragment hit. The optimization of the linker part was accomplished with the aid of MOE. The top molecule showed comparable cellular potency to ibrutinib and higher kinome selectivity. Abstract: Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.